Wen Xie

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (109)687.01 Total impact

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    ABSTRACT: The human pregnane X receptor (hPXR), a member of the nuclear receptor superfamily, senses xenobiotics and controls the transcription of genes encoding drug-metabolizing enzymes and transporters. The regulation of hPXR's transcriptional activation of its target genes is important for xenobiotic detoxification and endobiotic metabolism, and hPXR dysregulation can cause various adverse drug effects. Studies have implicated the putative phosphorylation site serine 350 (Ser(350)) in regulating hPXR transcriptional activity, but the mechanism of regulation remains elusive. Here we investigated the transactivation of hPXR target genes in vitro and in vivo by hPXR with a phosphomimetic mutation at Ser(350) (hPXR(S350D)). The S350D phosphomimetic mutation reduced the endogenous expression of cytochrome P450 3A4 (an hPXR target gene) in HepG2 and LS180 cells. Biochemical assays and structural modeling revealed that Ser(350) of hPXR is crucial for formation of the hPXR-retinoid X receptor alpha (RXRα) heterodimer. The S350D mutation abrogated heterodimerization in a ligand-independent manner, impairing hPXR-mediated transactivation. Further, in a novel humanized transgenic mouse model expressing the hPXR(S350D) transgene, we demonstrated that the S350D mutation alone is sufficient to impair hPXR transcriptional activity in mouse liver. This transgenic mouse model provides a unique tool to investigate the regulation and function of hPXR, including its non-genomic function, in vivo. Our finding that phosphorylation regulates hPXR activity has implications for development of novel hPXR antagonists and for safety evaluation during drug development. Copyright © 2015 Elsevier Inc. All rights reserved.
    Biochemical pharmacology 06/2015; DOI:10.1016/j.bcp.2015.06.018 · 4.65 Impact Factor
  • Peipei Lu, Wen Xie
    Hepatology 06/2015; DOI:10.1002/hep.27957 · 11.19 Impact Factor
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    ABSTRACT: Lamotrigine (LTG) is commonly used to control seizure in epilepsy patients and with referenced therapeutic windows in clinical practice. This study is to identify and characterize the function of genetic variants that influence the trough concentrations of LTG in epilepsy patients following monotherapy regimen (37.5–250 mg/d). Twelve single nucleotide polymorphisms (SNPs) involved in LTG metabolism and transport pathways, including UGT2B7, ABCB1, ABCG2, NR1I2 and HNF4α were genotyped in 140 Chinese epilepsy patients. Steady-state trough concentration of LTG was measured by a high-performance liquid chromatography method. Polymorphisms in ABCG2 rs2231142, rs3114020, HNF4α rs2071197 and ABCB1 rs1128503 were found to be associated with LTG CDR (concentration/dose normalized by body weight). In addition, multiple linear regression analysis revealed that ABCG2 rs2231142 had a remarkable effect on LTG concentrations which is stated to be 4.8% of the variability of LTG and may also help to interpret ethnic difference in LTG pharmacokinetics. Our findings provided new insights that SNPs of genes involved in the transport of LTG contribute to interpatient variation in LTG pharmacokinetics. Future studies are necessary to determine whether these SNPs can be used to provide LTG dosing guidance and influence seizure control and adverse reaction of LTG.
    Drug Metabolism and Pharmacokinetics 05/2015; DOI:10.1016/j.dmpk.2015.05.002 · 2.86 Impact Factor
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    ABSTRACT: Weight gain is the most frequent adverse effect of valproic acid (VPA) treatment, resulting in poor compliance and many endocrine disturbances. Similarities in the weight change of monozygotic twins receiving VPA strongly suggestes that genetic factors are involved in this effect. However, few studies have been conducted to identify the relevant genetic polymorphisms. Additionally, the causal relationship between the VPA concentration and weight gain has been controversial. Thus, we investigated the effects of SNPs in several appetite stimulation and energy homeostasis genes and the steady state plasma concentrations (Css) of VPA on the occurrence of weight gain in patients. A total of 212 epilepsy patients receiving VPA were enrolled. Nineteen SNPs in 11 genes were detected using Sequenom MassArray iPlex platform, and VPA Css was determined by HPLC. After six months of treatment, 20.28% of patients were found to gain a significant amount of weight (weight gained ≥ 7%). Three SNPs in leptin receptor (LEPR), ankyrin repeat kinase domain containing 1 (ANKK1) and α catalytic subunit of AMPK (PRKAA2) showed significant associations with VPA-induced weight gain (p<0.001, p=0.017 and p=0.020, respectively). After Bonferroni correction for multiple tests, the genotypic association of LEPR rs1137101, the allelic association of LEPR rs1137101 and ANKK1 rs1800497 with weight gain remained significant. However, the VPA Css in patents who gained weight were not significantly different from those who did not gain weight (p=0.121). LEPR and ANKK1 genetic polymorphisms may have value in predicting VPA-induced weight gain. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 03/2015; 18(7). DOI:10.1093/ijnp/pyv021 · 5.26 Impact Factor
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    ABSTRACT: The solute carrier family 13 member 5 (SLC13A5) is a sodium-coupled transporter that mediates cellular uptake of citrate, which plays important roles in the synthesis of fatty acids and cholesterol. Recently, the pregnane X receptor (PXR, NR1I2) initially characterized as a xenobiotic sensor, has been functionally linked to the regulation of various physiological processes that are associated with lipid metabolism and energy homeostasis. Here, we show that the SLC13A5 gene is a novel transcriptional target of PXR and altered expression of SLC13A5 affects lipid accumulation in human liver cells. The prototypical PXR activator rifampicin markedly induced the mRNA and protein expression of SLC13A5 in human primary hepatocytes. Utilizing cell-based luciferase reporter assays, electrophoretic mobility shift assays, and chromatin immunoprecipitation assays, we identified and functionally characterized two enhancer modules located upstream of the SLC13A5 gene transcription start site, that are associated with regulation of PXR-mediated SLC13A5 induction. Functional analysis further revealed that rifampicin can enhance lipid accumulation in human primary hepatocytes; and knockdown of SLC13A5 expression alone leads to significant decrease of the lipid content in HepG2 cells. Overall, our results uncover SLC13A5 as a novel target gene of PXR and may contribute to drug-induced steatosis and metabolic disorders in humans. The American Society for Pharmacology and Experimental Therapeutics.
    Molecular pharmacology 01/2015; 87(4). DOI:10.1124/mol.114.097287 · 4.12 Impact Factor
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    ABSTRACT: Nanocarriers have recently emerged as an attractive platform for the delivery of various types of therapeutics including anticancer agents. Previously, we developed an improved TPGS delivery system (PEG5K-VE2) which demonstrated improved colloidal stability and greater in vivo antitumor activity. Nevertheless, the application of this system is still limited by a relatively low drug loading capacity (DLC). In this study we report that incorporation of a fluorenylmethyloxycarbonyl (Fmoc) motif at the interfacial region of PEG5K-VE2 led to significant improvement of the system through the introduction of an additional mechanism of drug/carrier interaction. Doxorubicin (DOX) could be effectively loaded into PEG5K-Fmoc-VE2 micelles at a DLC of 39.9%, which compares favorably to most reported DOX nanoformulations. In addition, PEG5K-Fmoc-VE2/DOX mixed micelles showed more sustained release of DOX in comparison to the counterpart without Fmoc motif. MTT assay showed that PEG5K-Fmoc-VE2/DOX exerted significantly higher levels of cytotoxicity over DOX, Doxil as well as PEG5K-VE2/DOX in PC-3 and 4T1.2 cells. A cytotoxicity assay with NCI/ADR-RES, a drug resistant cell line, suggested that PEG5K-Fmoc-VE2 may have the potential to reverse multidrug resistance, which was supported by its inhibition of P-gp ATPase. Pharmacokinetic (PK) and biodistribution studies showed an increased half-life in blood circulation and more effective tumor accuulation for DOX formulated in PEG5K-Fmoc-VE2 micelles. More importantly, DOX-loaded PEG5K-Fmoc-VE2 micelles showed an excellent safety profile with a MTD (~ 30 mg DOX/kg) that is about 3 times as much as that for free DOX. Finally, superior antitumor activity was demonstrated by PEG5K-Fmoc-VE2/DOX in both drug-sensitive (4T1.2 and PC-3) and drug-resistant (KB 8-5) tumor models compared to DOX, Doxil, and PEG5K-VE2/DOX.
    Journal of Controlled Release 12/2014; 196. DOI:10.1016/j.jconrel.2014.10.016 · 7.26 Impact Factor
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    ABSTRACT: The constitutive androstane receptor (CAR) is initially defined as a xenobiotic nuclear receptor that protects the liver from injury. Detoxification of damaging chemicals is achieved by CAR-mediated induction of drug-metabolizing enzymes and transporters. More recent research has implicated CAR in energy metabolism, suggesting a therapeutic potential for CAR in metabolic diseases, such as type 2 diabetes and obesity. A better understanding of the mechanisms by which CAR regulates energy metabolism will allow us to take advantage of its effectiveness while avoiding its side effects. This review summarizes the current progress on the regulation of CAR nuclear translocation, upstream modulators of CAR activity, and the crosstalk between CAR and other transcriptional factors, with the aim of elucidating how CAR regulates glucose and lipid metabolism.
    Acta Pharmacologica Sinica 12/2014; 36(1). DOI:10.1038/aps.2014.102 · 2.50 Impact Factor
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    ABSTRACT: Altered expression of miR-29b is implicated in the pathogenesis and progression of liver fibrosis. We and others previously demonstrated that miR-29b down-regulates the expression of several extracellular-matrix (ECM) genes including Col 1A1, Col 3A1 and Elastin via directly targeting their 3’-UTRs. However, whether or not miR-29b plays a role in the post-translational regulation of ECM biosynthesis has not been reported. Heat shock protein 47 (HSP47) and lysyl oxidase (LOX) are known to be essential for ECM maturation. In this study we have demonstrated that expression of HSP47 and LOX was significantly up-regulated in culture-activated primary rat hepatic stellate cells (HSCs), TGF-β stimulated LX-2 cells and liver tissue of CCl4-treated mice, which was accompanied by a decrease of miR-29b level. In addition, over-expression of miR-29b in LX-2 cells resulted in significant inhibition on HSP47 and LOX expression. Mechanistically, miR-29b inhibited the expression of a reporter gene that contains the respective full-length 3’-UTR from HSP47 and LOX gene, and this inhibitory effect was abolished by the deletion of a putative miR-29b targeting sequence from the 3’-UTRs. Transfection of LX-2 cells with miR-29b led to abnormal collagen structure as shown by electron-microscopy, presumably through down-regulation of the expression of molecules involved in ECM maturation including HSP47 and LOX. These results demonstrated that miR-29b is involved in regulating the post-translational processing of ECM and fibril formation.
    Biochemical and Biophysical Research Communications 04/2014; 446(4). DOI:10.1016/j.bbrc.2014.03.037 · 2.28 Impact Factor
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    ABSTRACT: The estrogen sulfotransferase (EST/SULT1E1) is known to catalyze the sulfoconjugation and deactivation of estrogens. The goal of this study is to determine whether and how EST plays a role in human adipogenesis. By using human primary adipose derived stem cells (ASCs) and whole fat tissues from the abdominal subcutaneous fat of obese and non-obese subjects, we showed that the expression of EST was low in pre-adipocytes but increased upon differentiation. Overexpression and knockdown of EST in ASCs promoted and inhibited differentiation, respectively. The pro-adipogenic activity of EST in humans was opposite to the anti-adipogenic effect of the same enzyme in rodents. Mechanistically, EST promoted adipogenesis by deactivating estrogens. The pro-adipogenic effect of EST can be recapitulated by using an estrogen receptor (ER) antagonist or ERα knockdown. In contrast, activation of ER in ASCs inhibited adipogenesis by decreasing the recruitment of the adipogenic peroxisome proliferator activated receptor γ (PPARγ) onto its target gene promoters, whereas ER antagonism increased the recruitment of PPARγ to its target gene promoters. Linear regression analysis revealed a positive correlation between the expression of EST and body mass index (BMI), as well as a negative correlation between the ERα expression and BMI. We conclude that EST is a pro-adipogenic factor, which may serve as a druggable target to inhibit the turnover and accumulation of adipocytes in obese patients.
    Molecular and Cellular Biology 02/2014; DOI:10.1128/MCB.01147-13 · 5.04 Impact Factor
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    ABSTRACT: Bedaquiline is a recently approved drug for treatment of multi-drug resistant tuberculosis. Adverse cardiac and hepatic drug reactions of bedaquiline have been noted in clinical practice. The current study investigated bedaquiline metabolism in human hepatocytes using a metabolomic approach. Bedaquiline N-demethylation via cytochrome P450 3A4 (CYP3A4) was confirmed as the major pathway in bedaquiline metabolism. Besides CYP3A4, we found that both CYP2C8 and CYP2C19 contributed to bedaquiline N-demethylation. The Km values of CYP2C8, CYP2C19 and CYP3A4 in bedaquiline N-demethylation were 13.1, 21.3 and 8.5 μM, respectively. We also identified a novel metabolic pathway of bedaquiline that produced an aldehyde intermediate. In summary, this study extended our knowledge of bedaquiline metabolism, which can be applied to predict and prevent drug-drug interactions and adverse drug reactions associated with bedaquiline.
    Drug metabolism and disposition: the biological fate of chemicals 02/2014; 42(5). DOI:10.1124/dmd.113.056119 · 3.33 Impact Factor
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    ABSTRACT: The steroid sulfatase (STS)-mediated de-sulfation is a critical metabolic mechanism that regulates the chemical and functional homeostasis of endogenous and exogenous molecules. In this report, we first showed that the liver expression of Sts was induced in both the high-fat diet (HFD) and ob/ob models of obesity and type 2 diabetes and during the fed to fasting transition. In defining the functional relevance of STS induction in metabolic disease, we showed that over-expression of STS in the liver of transgenic mice alleviated HFD and ob/ob models of obesity and type 2 diabetes, including reduced body weight, improved insulin sensitivity, and decreased hepatic steatosis and inflammation. Interestingly, STS exerted its metabolic benefit through sex-specific mechanisms. In female mice, STS may have increased hepatic estrogen activity by converting biologically inactive estrogen sulfates to active estrogens and consequently improved the metabolic functions; whereas ovariectomy abolished this protective effect. In contrast, the metabolic benefit of STS in males may have been accounted for by the male-specific decrease of inflammation in white adipose tissue and skeletal muscle, as well as a pattern of skeletal muscle gene expression that favors energy expenditure. The metabolic benefit in male STS transgenic mice was retained after castration. Treatment with the STS substrate estrone sulfate also improved metabolic functions in both the HFD and ob/ob models. Our results have uncovered a novel function of STS in energy metabolism and type 2 diabetes. Liver-specific STS induction or estrogen/estrogen sulfate delivery may represent a novel approach to manage metabolic syndrome.
    Journal of Biological Chemistry 02/2014; 289(12). DOI:10.1074/jbc.M113.535914 · 4.60 Impact Factor
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    ABSTRACT: Sulfotransferase (SULT)-mediated sulfation represents a critical mechanism in regulating the chemical and functional homeostasis of endogenous and exogenous molecules. The cholesterol sulfotransferase SULT2B1b catalyzes the sulfoconjugation of cholesterol to synthesize cholesterol sulfate (CS). In this study, we showed that the expression of Sult2B1b in the liver was induced in obese mice and during the transition from the fasted to the fed state, suggesting that the regulation of SULT2B1b is physiologically relevant. CS and SULT2B1b inhibited gluconeogenesis by targeting the gluconeogenic hepatocyte nuclear factor 4α (HNF4α) in both cell cultures and transgenic mice. Treatment of mice with CS or transgenic overexpression of the CS-generating SULT2B1b in the liver inhibited hepatic gluconeogenesis and alleviated metabolic abnormalities in both the diet-induced obesity (DIO) and ob/ob mice. Mechanistically, CS and SULT2B1b inhibited gluconeogenesis by suppressing the expression of acetyl-CoA synthetase (Acss), leading to decreased acetylation and nuclear exclusion of HNF4α. Our results also suggested leptin as a potential effector of SULT2B1b in improving metabolic functions. We conclude that SULT2B1b and its enzymatic byproduct CS are important metabolic regulators that control glucose metabolism, suggesting CS as a potential therapeutic agent and SULT2B1b as a potential therapeutic target for metabolic disorders.
    Molecular and Cellular Biology 11/2013; DOI:10.1128/MCB.01094-13 · 5.04 Impact Factor
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    Dataset: cd36
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    ABSTRACT: To investigate the effects of three natural product compounds, carapin, santonin and isokobusone, on the activity of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in induction of drug-metabolizing enzymes and inhibition of inflammation. The monkey kidney-derived fibroblast (CV-1) cells and human embryonic kidney HEK293 cells were used for transient transfection and luciferase reporter gene assays. Human primary hepatocytes and primary hepatocytes from wild type, PXR-/-, and hPXR transgenic mice were used to study the induction of drug-metabolizing enzymes and the implication of these compounds in inflammation. Carapin, santonin and isokobusone activated both PXR and CAR in transient transfection and luciferase reporter gene assays. Mutagenesis studies showed that two amino acid residues, Phe305 of the rodent PXR and Leu308 of the human PXR, are critical for the recognition of these compounds by PXR. Importantly, the activation of PXR and CAR by these compounds induced the expression of drug-metabolizing enzymes in primary human and mouse hepatocytes. Furthermore, activation of PXR by these compounds inhibited the expression of inflammatory mediators in response to lipopolysaccharide (LPS). The effects of these natural compounds on drug metabolism and inflammation were abolished in PXR-/- hepatocytes. Our results show that carapin, santonin and isokobusone activate PXR and CAR and induce drug-metabolizing enzymes. In addition, these compounds inhibited the expression of inflammatory mediators in response to LPS through the activation of PXR.
    Pharmaceutical Research 07/2013; 30(9). DOI:10.1007/s11095-013-1101-9 · 3.95 Impact Factor
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    ABSTRACT: Farnesoid X receptor (FXR) has important roles in maintaining bile acid and cholesterol homeostasis. Here we report that the antiparasitic drug ivermectin is a ligand for nuclear FXR. We identify ivermectin using a high-throughput compound library screening and show that it induces the transcriptional activity of the FXR with distinctive properties in modulating coregulator recruitment. The crystal structure of ivermectin complexed with the ligand-binding domain of FXR reveals a unique binding mode of ivermectin in the FXR ligand-binding pocket, including the highly dynamic AF-2 helix and an expanded ligand-binding pocket. Treatment of wild-type mice, but not of FXR-null mice, with ivermectin decreases serum glucose and cholesterol levels, suggesting that ivermectin regulates metabolism through FXR. Our results establish FXR as the first mammalian protein targeted by ivermectin with high selectivity. Considering that ivermectin is a widely used clinical drug, our findings reveal a safe template for the design of novel FXR ligands.
    Nature Communications 06/2013; 4:1937. DOI:10.1038/ncomms2924 · 10.74 Impact Factor
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    ABSTRACT: Non-alcoholic steatohepatitis (NASH) is a liver disorder that still demands improved treatment. Understanding the pathogenesis of NASH will help to develop novel approaches to prevent or treat this disease. In this study, we revealed a novel function of the aryl hydrocarbon receptor (AhR) in NASH. Transgenic or pharmacological activation of AhR heightened animal sensitivity to NASH induced by the methionine and choline deficient (MCD) diet, which was reasoned to be due to increased hepatic steatosis, production of reactive oxygen species (ROS), and lipid peroxidation. Mechanistically, the increased ROS production in AhR-activated mouse liver was likely a result of a lower superoxide dismutase 2 (SOD2) activity and compromised clearance of ROS. Activation of AhR induced TCDD-inducible poly (ADP-ribose) polymerase (TiPARP) gene expression, depleted NAD+, deactivated the mitochondrial sirtuin deacetylase 3 (Sirt3), increased SOD2 acetylation, and thereby decreased SOD2 activity. We also showed that Sirt3 ablation sensitized mice to NASH, whereas adenoviral overexpression of Sirt3 alleviated the NASH phenotype in AhR transgenic mice. We conclude that activation of AhR sensitizes mice to NASH by facilitating both the "first hit" of steatosis and the "second hit" of oxidative stress. Our results suggest that the use of AhR antagonists might be a viable approach to prevent and treat NASH. Manipulation of the expression or activity of Sirt3 may also represent a novel approach to manage NASH.
    Molecular and Cellular Biology 03/2013; 33(10). DOI:10.1128/MCB.01658-12 · 5.04 Impact Factor
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    ABSTRACT: Aim: Cyclosporine requires close therapeutic drug monitoring because of its narrow therapeutic index and marked inter-individual pharmacokinetic variation. In this study, we investigated the associations of CYP3A4, CYP3A5, ABCB1, NFKB1, and NR1I2 polymorphisms with cyclosporine concentrations in Chinese renal transplant recipients in the early period after renal transplantation. Methods: A total of 101 renal transplant recipients receiving cyclosporine were genotyped for CYP3A4*1G, CYP3A5*3, ABCB1 C1236T, G2677T/A, C3435T, NFKB1 −94 ins/del ATTG, and NR1I2 polymorphisms. Cyclosporine whole blood levels were measured by a fluorescence polarization immunoassay. Trough concentrations of cyclosporine were determined for days 7-18 following transplantation. Results: The dose-adjusted trough concentration (C0) of cyclosporine in ABCB1 2677 TT carriers was significantly higher than that in GG carriers together with GT carriers [90.4±24.5 vs 67.8±26.8 (ng/mL)/(mg/kg), P=0.001]. ABCB1 3435 TT carriers had a significantly higher dose-adjusted C0 of cyclosporine than CC carriers together with CT carriers [92.0±24.0 vs 68.4±26.5 (ng/mL)/(mg/kg), P=0.002]. Carriers of the ABCB1 1236TT-2677TT-3435TT haplotype had a considerably higher CsA C0/D than carriers of other genotypes [97.2±21.8 vs 68.7±26.9 (ng/mL)/(mg/kg), P=0.001]. Among non-carriers of the ABCB1 2677 TT and 3435 TT genotypes, patients with the NFKB1 −94 ATTG ins/ins genotype had a significantly higher dose-adjusted C0 than those with the −94 ATTG del/del genotype [75.9±32.9 vs 55.1±15.1 (ng/mL)/(mg/kg), P=0.026]. Conclusion: These results illustrate that the ABCB1 and NFKB1 genotypes are closely correlated with cyclosporine trough concentrations, suggesting that these SNPs are useful for determining the appropriate dose of cyclosporine.
    Acta Pharmacologica Sinica 03/2013; 34(4). DOI:10.1038/aps.2012.200 · 2.50 Impact Factor
  • Mengxi Jiang, Wen Xie
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    ABSTRACT: The constitutive androstane receptor (CAR, NR1I3) is a member of the nuclear receptor superfamily. Initially recognized as a xenobiotic receptor, CAR has been increasingly appreciated for its endobiotic functions in influencing glucose and lipid metabolism, whose dysregulations are implicated in the most prevalent metabolic disorders, such as obesity and type 2 diabetes. Given the metabolic benefits of CAR activation, CAR may represent an attractive therapeutic target to manage obesity and type 2 diabetes. Further studies are necessary to understand the mechanisms of action of CAR in metabolic diseases and to determine the human relevance of the antidiabetic effect of CAR.
    Drug Metabolism Reviews 02/2013; 45(1):156-163. DOI:10.3109/03602532.2012.743561 · 6.29 Impact Factor
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    Wen Xie, John Y L Chiang
    Drug Metabolism Reviews 02/2013; 45(1):1-2. DOI:10.3109/03602532.2013.754577 · 6.29 Impact Factor
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    ABSTRACT: The pregnane X receptor (PXR), along with its sister receptor constitutive androstane receptor (CAR), was initially characterized as a xenobiotic receptor that regulates drug metabolism. In this study, we have uncovered an unexpected endobiotic role of PXR in obesity and type 2 diabetes. PXR ablation inhibited high fat diet (HFD)-induced obesity, hepatic steatosis, and insulin resistance, which were accounted for by increased oxygen consumption, increased mitochondrial β-oxidation, inhibition of hepatic lipogenesis and inflammation, and sensitization of insulin signaling. In an independent model, introducing the PXR-/- allele into the ob/ob background also improved body composition and relieved the diabetic phenotype. The ob/ob mice deficient of PXR showed increased oxygen consumption and energy expenditure, as well as inhibition of gluconeogenesis and increased rate of glucose disposal during euglycemic clamp. Mechanistically, the metabolic benefits of PXR ablation were associated with the inhibition of c-Jun N-terminal kinase (JNK) activation and down-regulation of lipin-1, a novel PXR target gene. The metabolic benefit of PXR ablation was opposite to the reported pro-diabetic effect of CAR ablation. Our results may help to establish PXR as a novel therapeutic target, and PXR antagonists may be used for the prevention and treatment of obesity and type 2 diabetes.
    Diabetes 01/2013; 62(6). DOI:10.2337/db12-1039 · 8.47 Impact Factor

Publication Stats

5k Citations
687.01 Total Impact Points

Institutions

  • 2002–2015
    • University of Pittsburgh
      • • Department of Pharmacology and Chemical Biology
      • • Center for Pharmacogenetics
      • • Pharmaceutical Sciences
      • • Department of Chemistry
      • • School of Pharmacy
      Pittsburgh, Pennsylvania, United States
  • 2008
    • Beijing Normal University
      Peping, Beijing, China
  • 2000–2002
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1999–2002
    • Salk Institute
      • Gene Expression Laboratory
      La Jolla, California, United States